CD163+ Macrophages Induce Endothelial-to-Mesenchymal Transition in Atheroma.

BACKGROUND: Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163+ macrophages. Here, we explored the hypothesis that CD163+ macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap. METHODS: Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone ApoE-/- and ApoE-/-/CD163-/- mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments. RESULTS: In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163+ macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa ß) signaling by proinflammatory cytokines released from CD163+ macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163+ macrophage-induced EndMT. Additionally, CD163 deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes. CONCLUSIONS: CD163+ macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.

Coronary Artery Calcification: Current Concepts and Clinical Implications.

Coronary artery calcification (CAC) accompanies the development of advanced atherosclerosis. Its role in atherosclerosis holds great interest because the presence and burden of coronary calcification provide direct evidence of the presence and extent of coronary artery disease; furthermore, CAC predicts future events independently of concomitant conventional cardiovascular risk factors and to a greater extent than any other noninvasive biomarker of this disease. Nevertheless, the relationship between CAC and the susceptibility of a plaque to provoke a thrombotic event remains incompletely understood. This review summarizes the current understanding and literature on CAC. It outlines the pathophysiology of CAC and reviews laboratory, histopathological, and genetic studies, as well as imaging findings, to characterize different types of calcification and to elucidate their implications. Some patterns of calcification such as microcalcification portend increased risk of rupture and cardiovascular events and may improve prognosis assessment noninvasively. However, contemporary computed tomography cannot assess early microcalcification. Limited spatial resolution and blooming artifacts may hinder estimation of degree of coronary artery stenosis. Technical advances such as photon counting detectors and combination with nuclear approaches (eg, NaF imaging) promise to improve the performance of cardiac computed tomography. These innovations may speed achieving the ultimate goal of providing noninvasively specific and clinically actionable information.

Subclinical Atherosclerosis: Part 1: What Is it? Can it Be Defined at the Histological Level?

While coronary artery disease remains a major cause of death, it is preventable. Therefore, the focus needs to shift to the early detection and prevention of atherosclerosis. Asymptomatic atherosclerosis is widely termed subclinical atherosclerosis, which is an early indicator of atherosclerotic burden, and understanding this disease is important because timely intervention could prevent future cardiovascular morbidity and mortality. We histologically recognize the earliest lesion of atherosclerosis as pathological intimal thickening, which is characterized by the presence of lipid pools. The difference between clinical atherosclerosis and subclinical atherosclerosis is whether the presence of atherosclerosis results in the clinical symptoms of ischemia, such as stroke, myocardial infarction, or chronic limb-threatening ischemia. In the absence of thrombosis, there are various types of histological plaque that encompass subclinical atherosclerosis: pathological intimal thickening, fibroatheroma, thin-cap fibroatheroma, plaque rupture, healed plaque ruptures, and fibrocalcific plaque. Plaque morphology that is most frequently responsible for acute coronary thrombosis is plaque rupture. Calcification of coronary arteries is the hallmark of atherosclerosis and is a predictor of future coronary events. Atherosclerosis occurs in other vascular beds and is most frequent in arteries of the lower extremity, followed by carotid, aorta, and coronary arteries, and the mechanisms leading to clinical symptoms are unique for each location.

Polygenic Risk Score Associates With Atherosclerotic Plaque Characteristics at Autopsy.

BACKGROUND: Polygenic risk scores (PRSs) for coronary artery disease (CAD) potentially improve cardiovascular risk prediction. However, their relationship with histopathologic features of CAD has never been examined systematically. METHODS: From 4327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner for sudden death between 1994 and 2015, 2455 cases were randomly selected for genotyping. We generated PRS from 291 known CAD risk loci. Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including %stenosis, calcification, thin-cap fibroatheromas, and thrombotic CAD. RESULTS: After exclusion of cases with insufficient DNA sample quality or with missing data, 954 cases (mean age, 48.8±14.7 years; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared with subjects in the lowest quintile, with greater %stenosis (80.3%±27.0% versus 50.4%±38.7%; adjusted P<0.001) and a higher frequency of calcification (69.6% versus 35.8%; adjusted P=0.004) and thin-cap fibroatheroma (26.7% versus 9.5%; adjusted P=0.007). Even after adjustment for traditional CAD risk factors, subjects within the highest PRS quintile had higher odds of severe atherosclerosis (ie, ≥75% stenosis; adjusted odds ratio, 3.77 [95% CI, 2.10-6.78]; P<0.001) and plaque rupture (adjusted odds ratio, 4.05 [95% CI, 2.26-7.24]; P<0.001). Moreover, subjects within the highest quintile had higher odds of CAD-associated cause of death, especially among those aged ≤50 years (adjusted odds ratio, 4.08 [95% CI, 2.01-8.30]; P<0.001). No statistically significant associations were observed with plaque erosion after adjusting for covariates. CONCLUSIONS: This is the first autopsy study investigating associations between PRS and atherosclerosis severity at the histopathologic level in subjects with sudden death. Our pathological analysis suggests PRS correlates with plaque burden and features of advanced atherosclerosis and may be useful as a method for CAD risk stratification, especially in younger subjects.

Comprehensive gene profiling of the metabolic landscape of humanized livers in mice.

BACKGROUND & AIMS: The human liver transcriptome is complex and highly dynamic, e.g. one gene may produce multiple distinct transcripts, each with distinct posttranscriptional modifications. Direct knowledge of transcriptome dynamics, however, is largely obscured by the inaccessibility of the human liver to treatments and the insufficient annotation of the human liver transcriptome at transcript and RNA modification levels. METHODS: We generated mice that carry humanized livers of identical genetic background and subjected them to representative metabolic treatments. We then analyzed the humanized livers with nanopore single-molecule direct RNA sequencing to determine the expression level, m6A modification and poly(A) tail length of all RNA transcript isoforms. Our system allows for the de novo annotation of human liver transcriptomes to reflect metabolic responses and for the study of transcriptome dynamics in parallel. RESULTS: Our analysis uncovered a vast number of novel genes and transcripts. Our transcript-level analysis of human liver transcriptomes also identified a multitude of regulated metabolic pathways that were otherwise invisible using conventional short-read RNA sequencing. We revealed for the first time the dynamic changes in m6A and poly(A) tail length of human liver transcripts, many of which are transcribed from key metabolic genes. Furthermore, we performed comparative analyses of gene regulation between humans and mice, and between two individuals using the liver-specific humanized mice, revealing that transcriptome dynamics are highly species- and genetic background-dependent. CONCLUSION: Our work revealed a complex metabolic response landscape of the human liver transcriptome and provides a novel resource to understand transcriptome dynamics of the human liver in response to physiologically relevant metabolic stimuli (https://caolab.shinyapps.io/human_hepatocyte_landscape/). IMPACT AND IMPLICATIONS: Direct knowledge of the human liver transcriptome is currently very limited, hindering the overall understanding of human liver pathophysiology. We combined a liver-specific humanized mouse model and long-read direct RNA sequencing technology to establish a de novo annotation of the human liver transcriptome and identified a multitude of regulated metabolic pathways that were otherwise invisible using conventional technologies. The extensive regulatory information on human genes we provided could enable basic scientists to infer the pathological relevance of their genes of interest and physician scientists to better pinpoint the changes in metabolic networks underlying a specific pathophysiology.

Effect of EDTA with porous balloon on calcified lesion: An atherosclerotic cadaver study.

BACKGROUND: Ethylene diamine tetra-acetic acid (EDTA) is a chelating agent used to dissolve calcium deposits but evidence in decalcifying atherosclerotic lesions is limited. AIMS: We assessed the feasibility and efficacy of EDTA delivered via porous balloon to target calcified lesions in cadaveric below-the-knee (BTK) arteries. METHODS: Using porcine carotid arteries, EDTA concentration was measured in the arterial wall and outside the artery at the 0-, 0.5-, 4-, and 24-h circulation after the injection through a porous balloon. In cadaver BTK samples, the proximal and distal anterior tibial artery (ATA) and distal posterior tibial artery (PTA) were studied. EDTA-2Na/H2O or EDTA-3Na/H2O were administrated using a porous balloon, then circulated for 6 h for EDTA-3Na/H2O and 24 h for EDTA-2Na/H2O and EDTA-3Na/H2O. Micro-CT imaging of the artery segments before and after the circulation and cross-sectional analyses were performed to evaluate calcium burden. RESULTS: In the porcine carotid study, EDTA was delivered through a porous balloon present in the arterial wall and was retained there for 24 h. In BTK arteries, cross-sectional analyses of micro-CT revealed a significant decrease in the calcium area in the distal ATA segment under 24-h circulation with EDTA-2Na/H2O and in the distal ATA segment under 24-h circulation with EDTA-3Na/H2O. The proximal ATA segment under 6-h circulation with EDTA-3Na/H2O showed no significant change in any parameters of calcium CONCLUSION: EDTA-3Na/H2O or EDTA-2Na/H2O with longer circulation times resulted in greater calcium reduction in atherosclerotic lesion. EDTA may have a potential therapeutic option for the treatment of atherosclerotic calcified lesions.

Comparison of thrombogenicity in different types of drug-eluting stents during transition from DAPT to SAPT.

BACKGROUND: During the transition from dual antiplatelet therapy (DAPT) to single antiplatelet therapy (SAPT), previous studies have raised concerns about a rebound effect. We compared platelet and inflammatory cell adhesion on different types of stents in the setting of clopidogrel presence and withdrawal. METHODS: In Experiment 1, three pigs were administered with DAPT, that is, clopidogrel and acetylsalicylic acid (ASA), for 7 days. Each animal underwent an extracorporeal carotid arteriovenous shunt model implanted with fluoropolymer-coated everolimus-eluting stent (FP-EES), biodegradable-polymer sirolimus-eluting stent (BP-SES), and biodegradable-polymer everolimus-eluting stents (BP-EES). In Experiment 2, two pigs were administered DAPT, clopidogrel was then withdrawn at day 7, and SAPT with ASA was continued for next 21 days. Then flow-loop experiments with the drawn blood from each time point were performed for FP-EES, BioLinx-polymer zotarolimus-eluting stents (BL-ZES), and BP-EES. The rebound effect was defined as the statistical increase of inflammation and platelet adhesion assessed with immunohistochemistry on the stent-strut level basis from baseline to day-14 or 28. RESULTS: Both experiments showed platelet adhesion value was highest in BP-EES, while the least in FP-EES during DAPT therapy. There was no increase in platelet or inflammatory cell adhesion above baseline values (i.e., no therapy) due to the cessation of clopidogrel on the stent-strut level. Monocyte adhesion was the least for FP-EES with the same trend observed for neutrophil adhesion. CONCLUSIONS: No evidence of rebound effect was seen after the transition from DAPT to SAPT. FP-EES demonstrated the most favorable antithrombotic and anti-inflammatory profile regardless of the different experimental designs.

Clonal Proliferation Within Smooth Muscle Cells in Unstable Human Atherosclerotic Lesions.

BACKGROUND: Studies in humans and mice using the expression of an X-linked gene or lineage tracing, respectively, have suggested that clones of smooth muscle cells (SMCs) exist in human atherosclerotic lesions but are limited by either spatial resolution or translatability of the model. METHODS: Phenotypic clonality can be detected by X-chromosome inactivation patterns. We investigated whether clones of SMCs exist in unstable human atheroma using RNA in situ hybridization (BaseScope) to identify a naturally occurring 24-nucleotide deletion in the 3'UTR of the X-linked BGN (biglycan) gene, a proteoglycan highly expressed by SMCs. BGN-specific BaseScope probes were designed to target the wild-type or deletion mRNA. Three different coronary artery plaque types (erosion, rupture, and adaptive intimal thickening) were selected from heterozygous females for the deletion BGN. Hybridization of target RNA-specific probes was used to visualize the spatial distribution of mutants. A clonality index was calculated from the percentage of each probe in each region of interest. Spatial transcriptomics were used to identify differentially expressed transcripts within clonal and nonclonal regions. RESULTS: Less than one-half of regions of interest in the intimal plaque were considered clonal with the mean percent regions of interest with clonality higher in the intimal plaque than in the media. This was consistent for all plaque types. The relationship of the dominant clone in the intimal plaque and media showed significant concordance. In comparison with the nonclonal lesions, the regions with SMC clonality had lower expression of genes encoding cell growth suppressors such as CD74, SERF-2 (small EDRK-rich factor 2), CTSB (cathepsin B), and HLA-DPA1 (major histocompatibility complex, class II, DP alpha 1), among others. CONCLUSIONS: Our novel approach to examine clonality suggests atherosclerosis is primarily a disease of polyclonally and to a lesser extent clonally expanded SMCs and may have implications for the development of antiatherosclerotic therapies.

Distal gastrectomy and Roux-en-Y reconstruction for refractory reflux esophagitis after proximal gastrectomy and esophagogastric anastomosis reconstruction.

Refractory gastroesophageal reflux disease can develop after proximal gastrectomy and esophagogastrostomy. We introduce a new method that combines distal gastrectomy and Roux-en-Y reconstruction to treat refractory reflux esophagitis in patients who have undergone proximal gastrectomy and esophagogastric anastomosis reconstruction. This novel method may be useful not only for alleviating the symptoms of gastroesophageal reflux disease but also for preventing future esophageal malignancies arising from long-term reflux esophagitis.

Induction of lung lesions by bronchial administration using bronchoscope technique in mice.

This study aimed to establish an exposure method that can induce homogeneous lesions with minimal inter-individual variability. The distribution of lesions induced by bleomycin (BLM) administration was also analyzed. C57BL mice were intrabronchially administered 20 µL of BLM (3 mg/mL) using a bronchoscope in the left or right bronchus. The mice were sacrificed 14 days after administration, and their lungs were evaluated histopathologically. BLM-induced inflammatory lesions were widely observed in the lungs. In the left bronchus-treated group, lesions were uniformly observed throughout the lobe, and no individual differences were noted. Meanwhile, in the right bronchus-treated group, individual differences in the distribution of the pulmonary lesions were observed. The distribution of lesions differed among the four lobes of the right lung owing to their anatomical features. Administration into the left bronchus is recommended for highly homogeneous lung exposure and for establishing models that contribute to highly accurate toxicity and efficacy evaluations.

Relationships between neighborhood disadvantage and cardiovascular findings at autopsy in subjects with sudden death.

BACKGROUND: Neighborhood disadvantage is associated with a higher risk of sudden cardiac death. However, autopsy findings have never been investigated in this context. Here, we sought to explore associations between neighborhood disadvantage and cardiovascular findings at autopsy in cases of sudden death in the State of Maryland. METHODS: State of Maryland investigation reports from 2,278 subjects within the CVPath Sudden Death Registry were screened for street addresses and 9-digit zip codes. Area deprivation index (ADI), used as metric for neighborhood disadvantage, was available for 1,464 subjects; 650 of whom self-identified as Black and 814 as White. The primary study outcome measurements were causes of death and gross and histopathologic findings of the heart. RESULTS: Subjects from most disadvantaged neighborhoods (i.e., ADI ≥ 8; n = 607) died at younger age compared with subjects from less disadvantaged neighborhoods (i.e., ADI ≤ 7; n = 857; 46.07 ± 14.10 vs 47.78 ± 13.86 years; P = 0.02) and were more likely Black or women. They were less likely to die from cardiac causes of death (61.8% vs 67.7%; P = 0.02) and had less severe atherosclerotic plaque features, including plaque burden, calcification, intraplaque hemorrhage, and thin-cap fibroatheromas. In addition, subjects from most disadvantaged neighborhoods had lower frequencies of plaque rupture (18.8% vs 25.1%, P = 0.004). However, these associations were omitted after adjustment for traditional risk factors and race. CONCLUSION: Neighborhood disadvantage did not associate with cause of death or coronary histopathology after adjustment for cardiovascular risk factors and race, implying that social determinants of health other than neighborhood disadvantage play a more prominent role in sudden cardiac death.

Local, Downstream, and Systemic Evaluation after Femoral Artery Angioplasty with Kanshas Drug-Coated Balloons In Vitro and in a Healthy Swine Model.

PURPOSE: To evaluate the incidence of distal embolism and local vascular responses after treatment with the Kanshas drug-coated balloon (DCB) in a preclinical model. MATERIALS AND METHODS: A total of 90 femoral arteries from 35 healthy swine were treated with a single-dose (×1) or triple-dose (×3) Kanshas DCB that applies the Unicoat technology with 3.2 µg/mm2 of paclitaxel. An uncoated Kanshas balloon was used as a control. The arterial wall, downstream skeletal muscle, and nontarget organs (kidneys, lungs, lymph nodes, liver, spleen, and heart) were histologically evaluated. For pharmacokinetic evaluation, a total of 40 healthy swine were treated with ×1 Kanshas DCB, and treated vessels were evaluated ex vivo with high-performance liquid chromatography-mass spectrometry. RESULTS: Arteries treated with the Kanshas DCB showed mild proteoglycan deposition accompanied by the loss of smooth muscle cells (SMCs). These changes increased in a dose-dependent manner (medial SMC loss at 28 days in the ×1 vs ×3 groups, in depth, 1 (0.75-1.38) vs 2 (1.63-2.44); P = .0008; in circumference, 0.83 (0.67-1) vs 1.5 (1.19-1.81); P = .0071). No evidence of distal embolization in skeletal muscles (0 of 210 histological sections) and nontarget organs (0 of 345 sections) was observed. The pharmacokinetic evaluation showed high paclitaxel concentration in the treated artery (912 ng/mg, peaking at 3 minutes), which remained detectable at up to 180 days (0.04 ng/mg). CONCLUSIONS: The Kanshas DCB showed a local drug effect in treated arteries up to 180 days with a high concentration of paclitaxel and no histological evidence of distal embolization.

Frequency and Distribution of Sheet and Nodular Calcification in Coronary Arteries in Japanese Patients.

Whether a nodular calcification (NC), which is the precursor to intracoronary thrombosis, is focally or diffusely distributed in the coronary tree has major implications for ongoing efforts to identify. This study aimed to investigate the frequency and spatial distribution patterns of sheet calcification (SC) and NC in a 3-vessel examination of autopsied human hearts.A total of 323 coronary artery specimens from 110 cadavers were obtained from autopsy cases. After fixation and decalcification, the coronary artery trees were cut every 5 mm into 4-µm transverse cross-sections for histological assessment. An SC was defined as a plate-like calcification of > 1 quadrant of the vessel or > 3 mm in diameter, and NC as nodular calcium deposits separated by fibrin, and a deposit size > 1 mm in diameter.Of the 6,306 histological cross-sections, SCs and NCs were identified in 1,627 (26%) and 233 (4%) cross-sections, respectively. SCs and NCs had a similar distribution pattern in all 3 coronary arteries. In the left anterior descending artery (LAD), NCs were predominantly located in the proximal segment: the first 45 mm from the LAD ostium (72%) and the first 60 mm from the LAD ostium (84%), respectively. However, NCs were evenly distributed throughout the length of the coronary artery in the right coronary artery (RCA) and left circumflex artery (LCX).NCs coexisted with SCs, and tended to cluster in predictable parts within the proximal segments of the LAD, but were evenly distributed throughout the RCA and LCX in coronary arteries from cadavers.

[A Case of Obstructive Rectal Cancer with Huge Liver Metastases Resected by the Liver-First Approach after Chemotherapy].

The patient was a 68-year-old woman without history of surgery. She presented with abdominal pain and leg edema. Ultrasound scan revealed hepatic masses. Colonoscopy and abdominal CT scan revealed unresectable rectal carcinoma with massive multiple liver metastases suspected of invasion of the inferior vena cava. After a transverse colon bi-pore colostomy, 10 courses of FOLFOX plus panitumumab therapy were administered, and the liver tumor was markedly reduced in size and determined to be PR by CT. Considering the possibility of unresectability due to the liver metastases re-growth, surgery was planned with liver-first approach(LFA). First, open resection of the right caudate lobe of the liver, combined resection of the IVC, combined resection of the diaphragm, partial hepatic S2 resection(2 sites), and cholecystectomy were performed, followed by laparoscopic anterior resection(D3)1 month later(R0). Postoperatively, the colostomy was closed after 8 courses of CapeOX(capecitabine alone from the middle of the course). Now the patient is alive and recurrence-free 4 years after the initial diagnosis. Conversion surgery with LFA after chemotherapy can be an effective treatment strategy for colorectal cancer with advanced liver metastases.

[A Case of Thoracic Esophageal Cancer Treated with COVID-19 Pneumonia during Preoperative Chemoradiotherapy(CRT)].

INTRODUCTION: There is concerned that prognosis of cancer-bearing patients is adversely affected by postponement of cancer treatment due to infection with a new type of coronavirus(COVID-19). We report a case of thoracic esophageal cancer treated with COVID-19 pneumonia during preoperative CRT. A 60-year-old female diagnosed as having Stage Ⅳ thoracic esophageal cancer(cT3N0M1LYM[104R])started receiving preoperative chemoradiotherapy. On the 12th day, she had a fever and was diagnosed with COVID-19 infection. CRT temporarily interrupted and she was treated for COVID-19 pneumonia preferentially. CRT was resumed promptly after remission. Finally, video-Assisted radical esophagectomy was performed. There were no postoperative complications. Nivolumab was started as an adjuvant therapy on the 2nd postoperative months. CONCLUSIONS: We experienced a case of thoracic esophageal cancer in which COVID-19 pneumonia was treated during preoperative CRT, and CRT and surgery were completed without complications by appropriate treatment.

[A Case of Hepatocellular Carcinoma Extending into Right Atrium Was Resected Successfully Using Cardiopulmonary Bypass].

A 59-year-old male was referred to our hospital for a thorough examination of liver function abnormality in the background of chronic hepatitis C. Abdominal contrast-enhanced CT showed multiple tumors in the right lobe of the liver, and an 8 cm tumor occupying S7, a tumor thrombus extending from the right hepatic vein to the inferior vena cava, and a tumor thrombus in the right branch of the portal vein. The patient was diagnosed with hepatocellular carcinoma, cT4N0M0, cStage ⅣA. After 5 courses of hepatic arterial infusion therapy, the intrahepatic lesion was significantly reduced, but micropulmonary metastasis appeared, and the tumor thrombus in the inferior vena cava increased to the thoracic inferior vena cava and just below the tricuspid valve. The patient had difficulty blocking blood flow in the inferior vena cava in the pericardial sac. The patient underwent right hepatectomy, tumor thrombus resection of the inferior vena cava, combined resection of the inferior vena cava, and bovine pericardial patch reconstruction under artificial cardiopulmonary support. He was discharged on the 23rd day after surgery and has been under outpatient observation for 16 months while receiving molecular-targeted drugs for lung metastasis.

[A Case of Advanced Gastric Cancer with Simultaneous Liver Metastasis for Long-Term Survival with Multimodal Therapy].

We report a case of advanced gastric cancer with simultaneous liver metastasis in which long-term survival has been obtained by multimodal therapy. Case 75-year-old, male. Esophagogastroduodenoscopy revealed advanced type 2 cancer in the greater curvature of the angular incisure. Computed tomography showed a single 20 mm mass was found in liver S2. Histopathological findings indicated that differentiated adenocarcinoma(tub1, HER2 3+). Diagnosis was gastric cancer, cT4aN0M1HEP, Stage Ⅳ. Tumor shrinkage was obtained after 2 courses of capecitabine/cisplatin/trastuzumab. Laparoscopic distal gastrectomy and partial liver resection was performed. Histopathological findings indicated tub1, ypT4aN0M1HEP, ypStage Ⅳ, grade 1a. A single 10 mm recurrence was observed in liver S1/2 13 months after first surgery. After chemotherapy, rehepatic resection was performed. Three years have passed since the last hepatectomy, and the patient is currently undergoing recurrence-free follow-up.

[A Case of Long-Term Survival with Multidisciplinary Treatment for Postoperative Local Recurrence of Intrahepatic Cholangiocarcinoma].

We report a case of local recurrence of intrahepatic bile duct cancer that was successfully treated using chemotherapy and radiation therapy. A man in his 80s underwent hepatic resection for intrahepatic cholangiocarcinoma, and abdominal CT 11 months after surgery revealed local recurrence around the dissected surface. He was diagnosed with a local recurrence of intrahepatic cholangiocarcinoma and started systemic chemotherapy(GEM plus CDDP plus S-1). After 11 courses of chemotherapy, stereotactic body radiation therapy(SBRT)was administered to the same site at 50 Gy/10 Fr, as the local recurrence area had increased, although no distant metastases were detected on imaging. The patient was then started on chemotherapy( GEM plus S-1), but after 2 courses, 8 courses of GEM alone were administered at the patient's request. No increase in tumor markers was observed, but an increase in the low-absorption area was observed on imaging. Thereafter, the regimen was changed to S-1. Three months later, the same area was reduced in size and obscured on imaging evaluation. The patient is still taking it 12 months later. No recurrence has been observed since 2 years and 7 months after the start of treatment for local recurrence. This case suggested that multidisciplinary therapy might be useful for local recurrence of intrahepatic cholangiocarcinoma.

[A Case of Rectal Cancer of Skin Metastasis Recurrence Near the Artificial Anus].

A 70s-year-old man visited the gastroenterologist with a complaint of bloody stool. Lower gastrointestinal endoscopy revealed a 50 mm type 0-Ⅰs+Ⅱa lesion in the center of the anterior wall of Rb in 4 cm from anal verge, and he was diagnosed with rectal cancer in cT1bcN0cM0, cStage Ⅰ. Endoscopic submucosal dissection was performed, but it was discontinued due to muscular traction, and was referred to our department at a later date for surgical purposes. Robot-assisted laparoscopic Hartmann's surgery(D2 dissection, sigmoid colon colostomy)was performed, and the pathological result was pT2pN0cM0, pStage Ⅰ with negative resection margins. Three months after the operation, a tumor was found on the left side of the stoma, and he visited us. Biopsy revealed the recurrence of skin metastasis of rectal cancer, and surgical procedure including colostomy and skin tumor resection, ileostomy, and colonic mucus fistula was performed. The patient was transferred to the hospital 3 months after the operation, but 2 months after the transfer, an increasing CEA was observed and CT revealed a local recurrence in the pelvis. Irradiation(45 Gy/15 times)was performed for the pain relief, but the general condition deteriorated thereafter and he died 8 months after the second operation.

[A Case of Conversion Surgery after Long-Term Chemotherapy for Pancreatic Cancer with Peritoneal Metastasis].

A 66-year-old woman was referred to the gastroenterology division of our hospital due to elevation of serum CEA level. Contrast-enhanced CT showed a hypovascular tumor at the body of pancreas. She was diagnosed with pancreatic cancer by EUS-FNA. By laparotomy, we found white nodules on mesentery and abdominal wall, which were diagnosed as peritoneal metastasis. After systemic chemotherapy with 9 courses of gemcitabine(GEM)plus nab-paclitaxel(PTX)and 30 courses of mFOLFIRINOX, the tumor had shrunk and serum CA19-9 level were remarkably decreased. Distal pancreatectomy was performed as conversion surgery. Pathological analysis revealed no remnant cancer cells in the primary tumor or the lymph nodes, confirming a pCR. S-1 was started as adjuvant chemotherapy, and she remains alive without recurrence 8 months after surgery.